The M60E4 is available briefly in the campaign, appearing only at the end of the level "Game Over". The enemy carrying it jumps out of the passenger's side of the first truck that is transporting troops to the battle (this truck will hit the brakes, ram a car, then reverse). This soldier will end up running to a destroyed green car at the far left hand side of the bridge. It is hard to obtain the M60E4 as it will be dropped near the BMP, and if the player tries to obtain it, the BMP is likely to kill them before they can retrieve it. This version of the M60E4 fires noticeably faster than in Multiplayer, with lower recoil. Also, one of Zakhaev's bodyguards is armed with one and he uses it to kill a SAS operative and to fire at the loyalist helicopter, but it is unobtainable.

For the brief time it is available in the campaign, the M60E4 is extremely powerful, killing in one shot, anywhere to the body, at any range.

In multiplayer, the M60E4 is unlocked at level 19. It can be equipped with a Red Dot Sight, a Grip or an ACOG Scope. It is also one of the few weapons with the option for golden camouflage, however this exclusivity is nullified in Call of Duty: Modern Warfare Remastered, as all weapons can accept Gold Camouflage. The M60E4 is the most powerful machine gun in multiplayer in terms of per-bullet damage, with one of the highest damage outputs per shot in the game, but has high recoil and a low rate of fire compared to the M249 SAW or RPD.

An unusual property of the M60E4 is that it suffers damage drop-off at range. Neither the M249 SAW nor the RPD suffer this, although it is likely for balance due to the M60E4's potential for a two-shot kill. The M60E4 is unique in suffering damage drop-off in Call of Duty: Modern Warfare; in Call of Duty: Modern Warfare Remastered it is joined in suffering damage drop-off with the Bered MK8 and the PKM.

The M60E4 is often used with the Double Tap or Stopping Power perks, with Stopping Power being more effective at long range and Double Tap being more effective at medium and close range. Stopping Power allows the M60E4 to kill with two shots at any distance, but does not reduce time to kill at short range; Double Tap, on the other hand, has superior killing speed over stopping power for the M60E4 at close range, but increases recoil. In practice, the RPD is superior to the M60E4 at long range, with or without Stopping Power, due to its slightly faster default firing rate and its lower recoil. However the M60E4 is superior at close range with Double Tap as Double Tap increases its rate of fire past that of the RPD's while retaining a two hit kill.

Like most light machine guns in the game, the M60E4 has a large belt capacity of 100 rounds but also suffers from a slow reload time of nearly 10 seconds and slow speed when switching to it. Thanks to its high damage per shot, some players use Sleight of Hand rather than Stopping Power in order to cut down on reload time. The M60E4 with the grip attachment is less popular because of the large, obstructive iron sights; however, it significantly reduces the high recoil of the gun. To compound the weakness of the iron sights, the M60E4 has extremely obstructive muzzle flash, making tracking targets at range near impossible.

In Hardcore, the M60E4 always kills in one shot at any range regardless of any factors such as Juggernaut or light cover. However, the low rate of fire causes it to suffer in this regard, as faster-firing weapons are more likely to land successful shot first.

The M60E4 is unlocked at level 72 in as the last light machine gun to be unlocked. It features extremely high power up close (a 2 shot kill anywhere up to 18 meters), but a slow rate of fire and the slowest reload time of any LMG. It is also the primary weapon equipped with the Juggernaut pointstreak, along with the MP412.

The M60E4's iron sights are regarded as extremely bulky and difficult to use at long ranges. Therefore, a Red Dot Sight or Holographic Sight is extremely useful when engaging targets at long range. Recoil can be compensated for by using Kick or the Gripattachment. Rapid Fire can be an interesting choice, as it allows a player to dispatch enemies very quickly at close to medium range; however, recoil is also dramatically increased, as the low rate of fire is supposed to counteract what is supposed to be very large recoil. Using Kick or the Attachments Proficiency to pair the Grip with Rapid Fire can mitigate this somewhat. The M60E4, like in previous games, is the only fully automatic weapon in the game that is capable of killing in two shots without any perk modification, excluding the USAS 12, Skorpion (from Call of Duty 4: Modern Warfare and Black Ops), and AA-12. It is very good for taking down air support due to its high damage. If combined with Blind Eye Pro perk, it becomes even better for that task. Like the PKP Pecheneg, this weapon cannot mount a Heartbeat Sensor, which can frustrate some players who use it on other LMGs.

As with the rest of the LMGs, the M60E4 has a slight increase to its minimum damage in a Title Update, making it require only three shots at most to kill an enemy (where as before was four).

Overall, the M60E4 is a solid choice, however, there are disadvantages. Rapid fire increases its effectiveness in close quarters however this also increases recoil. The grip can counter this, however without an optic it is difficult to engage targets at long range, making attachment choices an important process.

The M60E4 is available in Survival Mode at level 12 and costs $7000. The early unlock and high damage makes it useful against Juggernauts and heavy commando troops, along with helicopters, but Sleight of Hand is recommended, as the slow reload becomes a problem.